ATP-dependent Na+—K+ pump is a transmembrane enzyme, found in almost all cells of higher organisms, that is responsible for the active transport of sodium ions out of cells in exchange for extracellular potassium ions against their respective electrochemical gradients. A key function of the Na+—K+ pump is to generate the gradients required to maintain the resting membrane potential of electrically excitable cells. These gradients have important additional roles in driving the transmembrane transport of other ions and organic compounds, such as calcium and glucose, and in regulating cell volume.
Na+—K+ pump dysfunction is important in heart failure, cardiac ischaemia and vascular dysfunction. The pump maintains low intracellular Na+ levels and in turn drives Ca2+ efflux via the Na+—Ca2+ exchanger. Inhibition of the cardiac Na+—K+ pump results in abnormally elevated intracellular Na+ levels that disturb Ca2+ balance, leading to impaired contractility and arrhythmias in the case of heart failure and cardiac ischaemia, and altered vascular tone. Approaches to reverse Na+—K+ pump inhibition may be a useful therapeutic strategy.
Reactive oxygen species (ROS) are generated as a by-product of normal metabolic reactions in the body and subsequently can cause extensive damage to proteins, lipids, and DNA.
Oxidative stress plays a large role in cardiovascular pathophysiology, including atherosclerosis, hypertension, cardiomyopathy, and chronic heart failure in humans. Strenuous physical exercise also results in oxidative damage in the circulatory system as a result of elevated ROS levels during exercise. Oxidative stress also has a role in the pathophysiology of diabetes, renal failure, neurological and inflammatory disorders, ageing, cancer and hypertension. However, biomarkers of oxidative stress have generally not been particularly successful due to the technical difficulties in measuring oxidative stress in the circulation, or at the organ level, in vivo.
A number of biochemical markers of CVD, such as troponin I and T, are now commonly used in clinics to measure myocardial damage. However, the majority of the existing markers are useful only in the end stages of the disease where few successful intervention options exist.
The prevalence and impact of cardiac dysfunction continues to escalate. Identification of those at risk of heart failure, or those with mild, but undiagnosed heart failure will assist in earlier and more cost-effective application of therapies—prior to the development of disabling symptoms and costly hospitalization. Furthermore, identification of negative prognostic factors in individuals with heart failure or CVD may allow physicians to target aggressive therapeutic options. Since a large number of individuals experience a transient underlying developing pathology long before the signs or symptoms of CVD become apparent, there is a requirement for new markers that can describe the early tissue-specific, matrix remodelling process which ultimately leads to disease, and to link these markers to their intervention point along the cardiovascular continuum. Given the role oxidative stress plays in cardiovascular pathophysiology, an object of the present invention is to provide a biomarker that reflects oxidative stress. Such a marker would then be able to act as an “integrator” for many of the conventional risk factors for cardiovascular disease that are united by their mediation via ROS, as well as many other “difficult-to-define” risk factors.